Breast carcinoma (BrCa), which is the second most prevalent cancer in women, is a complex, inadequately understood, and often fatal disease when not detected at early stages. A more detailed understanding of the molecular mechanisms and regulatory pathways at work will enormously assist in improving the design and target selection of therapeutic strategies. MicroRNAs (miRNAs) are evolutionary conserved, short non-coding regulatory RNAs that post- transcriptionally modulate gene expression by binding to their cognate target mRNAs via pervasive and versatile mechanisms. Altered expression of specific subsets of miRNAs has been linked to different types of hematologic and solid tumors. Independent studies using BrCa clinical specimens have identified a small subset of miRNAs, which are differentially detected between normal and tumor tissue specimens. Thus, the clinical value of these miRNAs as novel biomarkers for different aspect of BrCa management is being actively investigated. Importantly, functional analyses in cell line systems and xenograft transplantation in mouse models have revealed tumor suppressive and oncogenic functions of some of these miRNAs. This proposal focuses on miRNAs as potential tumor suppressive mechanisms to prevent breast carcinogenesis. We will utilize a genetic approach in mouse models of BrCa to test the hypothesis that global impairment of miRNA functions enhances tumor growth and aggressiveness. Of note, our experimental strategy will be similar to the one successfully used by Tyler Jacks and colleagues to uncover tumor suppressive roles of miRNAs in a K-Ras-driven mouse model of lung cancer. We will target chromosomal deletion of miRNA- processing enzyme Dicer in mammary gland epithelia using the Cre/LoxP system. The effects of global loss of miRNA functions will be studied in well-established mouse models of BrCa. Mammary gland restricted expression of Polyoma virus middle T antigen (PyMT), Neu/HER-2 or Wnt-1 causes BrCa with different latencies and histological features reminiscent of specific human BrCa subtypes. We expect that results of this proposal will uncover an etiological contribution of miRNAs and validate the use of these mouse models for future studies concentrating on the role of individual miRNA in BrCa and development of miRNA-based therapeutic strategies. PUBLIC HEALTH RELEVANCE: MicroRNAs are a recently-discovered class of short non-coding RNA genes, which act as post-transcriptional negative regulators of gene expression. microRNA-mediated regulation of tumorigenesis is emerging as a new paradigm in the field of cancer biology. Our implemented in situ hybridization technology offers spatial resolution of miRNA expression unsurpassed by other techniques, which could be readily adapted to routine clinical practice to benefit patients and assist physicians in making crucial decisions.